In silico analysis of deleterious SNPs of human MTUS1 gene and their impacts on subsequent protein structure and function

Rozario, Liza Teresa; Sharker, Tanima; Nila, Tasnin Akter

doi:10.1371/journal.pone.0252932

Cited by 27 publications

(16 citation statements)

References 56 publications

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“…The function, activity, and regulation of a protein are closely tied to its structural stability. When stability decreases, proteins undergo degradation, misfolding, and clumping, leading to eventual dysfunction [ 48 ]. To evaluate the impact of the 16 harmful nsSNPs on the stability of the GRIN2A protein, the nsSNPs were first analyzed using 3D structures of the mutated domains.…”

Section: Discussionmentioning

confidence: 99%

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein’s structure and function

Ahammad¹,

Jamal²,

Bhattacharjee³

et al. 2023

PLoS ONE

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GRIN2A is a gene that encodes NMDA receptors found in the central nervous system and plays a pivotal role in excitatory synaptic transmission, plasticity and excitotoxicity in the mammalian central nervous system. Changes in this gene have been associated with a spectrum of neurodevelopmental disorders such as epilepsy. Previous studies on GRIN2A suggest that non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein’s structure and function. To gain a better understanding of the impact of potentially deleterious variants of GRIN2A, a range of bioinformatics tools were employed in this study. Out of 1320 nsSNPs retrieved from the NCBI database, initially 16 were predicted as deleterious by 9 tools. Further assessment of their domain association, conservation profile, homology models, interatomic interaction, and Molecular Dynamic Simulation revealed that the variant I463S is likely to be the most deleterious for the structure and function of the protein. Despite the limitations of computational algorithms, our analyses have provided insights that can be a valuable resource for further in vitro and in vivo research on GRIN2A-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein’s structure and function

Ahammad¹,

Jamal²,

Bhattacharjee³

et al. 2023

PLoS ONE

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“…PhD-SNP 92 is another tool that utilizes SVM to predict neutral or disease-associated SNPs 93 . Based on a neural network classifier, SNAP2 predicts nsSNP-induced changes in secondary structure 94 , and distinguishes between the effects of neutral to deleterious SNPs by considering the solvent accessibility effect, secondary structure, and evolutionary conservation 95 .…”

Section: Methodsmentioning

confidence: 99%

Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function

Dash

Munni

Mitra

et al. 2022

Sci Rep

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Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extracellular domain of TREM2. However, the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in TREM2 on disease progression remain unknown. In this study, we identified several high-risk nsSNPs in the TREM2 gene using various deleterious SNP predicting algorithms and analyzed their destabilizing effects on the ligand recognizing region of the TREM2 immunoglobulin (Ig) domain by molecular dynamics (MD) simulation. Cumulative prediction by all tools employed suggested the three most deleterious nsSNPs involved in loss of TREM2 function are rs549402254 (W50S), rs749358844 (R52C), and rs1409131974 (D104G). MD simulation showed that these three variants cause substantial structural alterations and conformational remodeling of the apical loops of the TREM2 Ig domain, which is responsible for ligand recognition. Detailed analysis revealed that these variants substantially increased distances between apical loops and induced conformation remodeling by changing inter-loop nonbonded contacts. Moreover, all nsSNPs changed the electrostatic potentials near the putative ligand-interacting region (PLIR), which suggested they might reduce specificity or loss of binding affinity for TREM2 ligands. Overall, this study identifies three potential high-risk nsSNPs in the TREM2 gene. We propose further studies on the molecular mechanisms responsible for loss of TREM2 function and the associations between TREM2 nsSNPs and neurodegenerative diseases.

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“…Mutations arising due to West syndrome were found in the re-entrant pore-forming domain, while ID and focal epilepsy mutations were found in the glutamate-binding domain S1 [ 3 ]. In recent times, SNPs in coding and regulatory areas were employed as markers in association and linkage studies to determine the region of the genome associated with a certain disease [ 15 , 16 , 17 , 18 , 19 ]. Because each variation has the potential to modify a protein’s function or structure, SNP detection studies and mutagenesis analysis are carried out together to uncover amino acid variations in protein-coding domains [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Role of Pathogenic nsSNPs in GRIN2B Gene Provoking Neurodevelopmental Disorders

Shah

Amjad

Hassan

et al. 2022

Genes

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The GluN2B subunit of N-methyl-D-aspartate receptors plays an important role in the physiology of different neurodevelopmental diseases. Genetic variations in the GluN2B coding gene (GRIN2B) have consistently been linked to West syndrome, intellectual impairment with focal epilepsy, developmental delay, macrocephaly, corticogenesis, brain plasticity, as well as infantile spasms and Lennox–Gastaut syndrome. It is unknown, however, how GRIN2B genetic variation impacts protein function. We determined the cumulative pathogenic impact of GRIN2B variations on healthy participants using a computational approach. We looked at all of the known mutations and calculated the impact of single nucleotide polymorphisms on GRIN2B, which encodes the GluN2B protein. The pathogenic effect, functional impact, conservation analysis, post-translation alterations, their driving residues, and dynamic behaviors of deleterious nsSNPs on protein models were then examined. Four polymorphisms were identified as phylogenetically conserved PTM drivers and were related to structural and functional impact: rs869312669 (p.Thr685Pro), rs387906636 (p.Arg682Cys), rs672601377 (p.Asn615Ile), and rs1131691702 (p.Ser526Pro). The combined impact of protein function is accounted for by the calculated stability, compactness, and total globularity score. GluN2B hydrogen occupancy was positively associated with protein stability, and solvent-accessible surface area was positively related to globularity. Furthermore, there was a link between GluN2B protein folding, movement, and function, indicating that both putative high and low local movements were linked to protein function. Multiple GRIN2B genetic variations are linked to gene expression, phylogenetic conservation, PTMs, and protein instability behavior in neurodevelopmental diseases. These findings suggest the relevance of GRIN2B genetic variations in neurodevelopmental problems.

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In silico analysis of deleterious SNPs of human MTUS1 gene and their impacts on subsequent protein structure and function

Cited by 27 publications

References 56 publications

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein’s structure and function

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein’s structure and function

Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function

Molecular Insights into the Role of Pathogenic nsSNPs in GRIN2B Gene Provoking Neurodevelopmental Disorders

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